Lo Cicero was included in Italy's squad for the 1999 Rugby World Cup but did not see any action and had to wait until the following year to make his international debut. It came against England in 2000 when he had the difficult task of filling the gap left by the Azzurri prop and captain Massimo Cuttitta.

He was named in the BBC's dream XV at the 2004 Six Nations Championship and was part of the Barbarians squad to take on New Zealand later that year. Lo Cicero was the only European player to receive a call, and he capped the feat by scoring a try. In 2005 he again represented the Barbarians for their matches against Scotland and England.

Lo Cicero won his 100th cap for Italy against Scotland in the 2013 Six Nations tournament and his 101st in the match against Wales, equalling Alessandro Troncon's record as Italy's most-capped player, breaking that record against England. Lo Cicero announced he was retiring from the Italian national team after their final game of the 2013 Six Nations against Ireland, and came on to massive cheers from Italian fans. Italy went on to win the game 22-15, thus recording their first Six Nations victory over Ireland.